Role of Complement Receptor Activation in a Mixed Dementia Model

补体受体激活在混合痴呆模型中的作用

• 批准号: 10585080
• 负责人: SALLY ANN FRAUTSCHY
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585080
• 关键词: Acceleration; Address; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Animal Model; Animal Testing; Area; Astrocytes; Atrophic; Attenuated; Automobile Driving; Behavior; Biochemical; Biological Availability; Biological Markers; Blocking Antibodies; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain-Derived Neurotrophic Factor; Breeding; Budgets; Caregivers; Cerebral small vessel disease; Cerebrovascular Disorders; Characteristics; Chronic; Clinical; Clinical Data; Combined Modality Therapy; Complement; Complement 3 Convertase; Complement 3b; Complement 5a; Complement Activation; Complement Receptor; Complex; Data; Dementia; Demyelinations; Development; Diagnosis; Disease; Dissection; Drug Design; Encephalitis; Euthanasia; Executive Dysfunction; Exhibits; Extravasation; Feedback; Female; Funding; Genes; Genetic Transcription; Glial Fibrillary Acidic Protein; Gliosis; Health; Hemorrhage; Hippocampus; Histologic; Histology; Human; Hypertension; Hypoxia; Image; Impaired cognition; Inflammation; Inflammatory; K-18 conjugate; Knowledge; Label; Lasers; Lesion; Letters; Liquid substance; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Mediating; Medicare; Methods; Microglia; Microscopy; Microvascular Dysfunction; Minor; Modeling; Mus; Nerve Degeneration; Neurons; Oral; Oral Administration; Outcome; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Plasma; Play; Prefrontal Cortex; Process; Protein Isoforms; Proteins; Randomized; Rat Transgene; Rattus; Receptor Activation; Resistance; Risk; Risk Factors; Role; Scanning; Serial Magnetic Resonance Imaging; Serum; Signal Transduction; Solid; Stroke; Structure; Study models; Subarachnoid Hemorrhage; Tauopathies; Testing; Thalamic structure; Therapeutic; Time; Transgenic Organisms; Treatment Efficacy; Validation; Vascular Cognitive Impairment; Vascular Dementia; Veterans; aged; antagonist; behavior test; biomarker validation; complement C5b; complement pathway; design; differential expression; drug development; early onset; familial Alzheimer disease; global health; hypertensive; improved; inflammatory marker; inhibitor; insight; interest; male; mitochondrial dysfunction; mixed dementia; monomer; mouse model; multidisciplinary; myelination; neuroimaging; neuroinflammation; neuron loss; neuropathology; neuroprotection; neurotoxic; neurovascular unit; normotensive; novel; novel therapeutics; pharmacokinetics and pharmacodynamics; putamen; response; sex; small molecule inhibitor; synergism; tau Proteins; tau aggregation; transcriptome sequencing; white matter; white matter damage

The coexistence of Alzheimer (AD) and cerebrovascular disease (CBVD), which defines Mixed Dementia (MxD) is present in many, if not most, of those diagnosed with AD. Hypertension is the major risk factor contributing to CBVD, driving small vessel disease (SVD), associated with white matter (WM) lesions characteristic of MxD, but the paucity of MxD models limits progress to understand mechanisms and advance therapeutics for this common disease. For example, drugs developed to clear amyloid (Abeta) may exacerbate CBVD, and fail to target poorly understood synergism between AD and CBVD. Our novel rat MxD model exhibits coexisting vascular and AD pathologies (AD transgenic), whereby hypertension and SVD exacerbate AD- associated aberrant neuroinflammation, mitochondrial dysfunction and tauopathy (Denver et al. 2019). Since recent clinical data, showing that WM damage is associated with the spread of tauopathy, not Abeta (Kapasi et al., 2022), this further validates our model. Further new data on seeding of MxD rats with tau fibrils, recapitulates tau spreading seen in human AD/MxD. The model was produced by breeding the Tg AD into a SHR-Stroke prone (SHRSP) rat background, the most widely studied model for vascular cognitive impairment and SVD, which exhibits a compromised neurovascular unit. Unlike mice, rats express all 6 tau isoforms and are more suitable than mice for complex imaging and behavioral testing, and assessing fluid biomarkers. The central hypotheses are: a) Complement factors are major components synergistically driving MxD and AD, and b) there is a positive feedback loop between tau pathogenesis and complement activation such that antagonizing either tau aggregation with structure-based inhibitors (Aim 2) or the complement cascade (Aim 3) will disproportionately reduce WM damage, tauopathy and executive function deficits in the hypertensive MxD model. Aim 1 will identify key MRI and laser captured pathology RNA expression profiles. 1A examines longitudinal changes of translatable MRI imaging measures (including SVD, demyelination, atrophy, and BBB leakage) that distinguish MxD from AD. In 1B, we perform IHC-guided laser capture microscopy dissection (LCM) and RNA seq in these MRI-characterized rats in 3 regions representing increased tauopathy (hippocampus), demyelination/WMH (dorsolateral/prefrontal cortex) and SVD (thalamus/putamen) to define MxD-specific, lesion- related pathways. Aims 2 and 3 investigate how AD and hypertension interact to influence a positive feedback loop between complement and tauopathy. Aim 2 uses a structure-based tau aggregation inhibitor that we characterized in tau mouse models. Aim 3 uses a state-of-the-art orally bioavailable and brain penetrant small molecule inhibitor (see letters), to investigate the causal role of C5aR activation that can drive tauopathy, BBB breakdown and WM loss. Outcomes. Outcomes focus on regional biochemical and histological changes in BBB, myelination, neurodegeneration, neuroinflammation and executive function deficits. CSF/plasma biomarkers are assessed: specifically validated AD biomarkers (ptau, NFL, Abeta40/42) and those associated with brain inflammation (GFAP, AQP4 (astrocytic endfoot protein)) or WMH (complement factors C3b, and Bb) and neuroprotection (BDNF) to identify their role in the tau-complement C5a feedback loop. Interpretation: Advances may include demonstration of hypertension-enhanced tauopathy and/or C5aR and tauopathy-enhanced BBB breakdown and one or more effective new treatments. Alternatively, tau aggregate inhibitors may not impede BBB and inflammatory pathogenesis, suggesting a minor role for the tau-inflammation-BBB loop and arguing for combination therapies. Which upstream C3-related inflammatory or downstream C5b components are inhibited by C5aR inhibitors will provide important insight into tau-complement feedback interactions in MxD. RNAseq is likely to fill major knowledge gaps in understanding mechanisms of SVD that drive conversion from AD pathology to onset of cognitive decline. Our proposal is strengthened by a multidisciplinary team with expertise in stroke, MRI imaging, LCM /RNAseq, complement activation, CBVD/AD neuropathology, and executive dysfunction.

阿尔茨海默病 (AD) 和脑血管疾病 (CBVD) 共存，定义为混合性痴呆 (MxD) 存在于许多（如果不是大多数）诊断患有 AD 的患者中。高血压是主要危险因素 导致 CBVD，导致小血管疾病 (SVD)，与白质 (WM) 病变相关 MxD 的特征，但 MxD 模型的缺乏限制了理解机制和推进的进展 针对这种常见疾病的治疗方法。例如，开发用于清除淀粉样蛋白（Abeta）的药物可能会加剧 CBVD，并且未能针对 AD 和 CBVD 之间人们知之甚少的协同作用。我们的新型大鼠 MxD 模型展示 共存的血管和 AD 病理（AD 转基因），高血压和 SVD 会加剧 AD- 相关的异常神经炎症、线粒体功能障碍和 tau 蛋白病 (Denver et al. 2019)。自从 最近的临床数据表明，WM 损伤与 tau 蛋白病的扩散相关，而不是 Abeta（Kapasi 等） al., 2022），这进一步验证了我们的模型。关于用 tau 纤维接种 MxD 大鼠的更多新数据，概括如下 在人类 AD/MxD 中观察到 tau 扩散。该模型是通过将 Tg AD 培育成 SHR-Stroke 生成的 倾向（SHRSP）大鼠背景，血管性认知障碍和 SVD 研究最广泛的模型， 它表现出神经血管单位受损。与小鼠不同，大鼠表达所有 6 种 tau 亚型，并且更 比小鼠更适合复杂的成像和行为测试以及评估液体生物标志物。中央 假设是：a) 补体因子是协同驱动 MxD 和 AD 的主要成分，b) 存在 是 tau 发病机制和补体激活之间的正反馈循环，从而拮抗任一 tau 与基于结构的抑制剂（目标 2）或补体级联（目标 3）的聚集将不成比例 减少高血压 MxD 模型中的 WM 损伤、tau 蛋白病变和执行功能缺陷。目标 1 将确定 关键 MRI 和激光捕获的病理 RNA 表达谱。 1A检查了纵向变化 可转化的 MRI 成像测量（包括 SVD、脱髓鞘、萎缩和 BBB 渗漏）可区分 来自 AD 的 MxD。在 1B 中，我们进行 IHC 引导的激光捕获显微镜解剖 (LCM) 和 RNA seq 这些 MRI 表征的大鼠的 3 个区域代表 tau 蛋白病变（海马体）增加， 脱髓鞘/WMH（背外侧/前额皮质）和 SVD（丘脑/壳核）来定义 MxD 特异性、病变 相关途径。目标 2 和 3 研究 AD 和高血压如何相互作用以影响正反馈 补体和tau蛋白病之间的循环。目标 2 使用基于结构的 tau 聚集抑制剂 tau 小鼠模型中的特征。 Aim 3 使用最先进的口服生物可利用和脑渗透剂小 分子抑制剂（见字母），研究可驱动 tau 蛋白病、BBB 的 C5aR 激活的因果作用 击穿和 WM 损失。结果。结果集中于 BBB 的区域生化和组织学变化， 髓鞘形成、神经变性、神经炎症和执行功能缺陷。 CSF/血浆生物标志物是 评估：经过专门验证的 AD 生物标志物（ptau、NFL、Abeta40/42）以及与大脑相关的生物标志物 炎症（GFAP、AQP4（星形细胞终足蛋白））或 WMH（补体因子 C3b 和 Bb）以及 神经保护 (BDNF) 以确定其在 tau 补体 C5a 反馈环中的作用。解读：进展 可能包括高血压增强的 tau 病和/或 C5aR 以及 tau 病增强的 BBB 的表现 分解和一种或多种有效的新疗法。或者，tau 聚集抑制剂可能不会阻碍 BBB 和炎症发病机制，表明 tau-炎症-BBB 环发挥次要作用，并争论 联合疗法。哪些上游 C3 相关炎症或下游 C5b 成分受到抑制 C5aR 抑制剂的研究将为 MxD 中 tau 补体反馈相互作用提供重要的见解。 RNA测序是 可能会填补理解 SVD 机制（推动 AD 病理学转变）方面的主要知识空白 认知能力下降的开始。我们的建议得到了具有中风专业知识的多学科团队的支持， MRI 成像、LCM /RNAseq、补体激活、CBVD/AD 神经病理学和执行功能障碍。